Dispensing device

ABSTRACT

A dispensing device having a storage device and an air pump for dispensing a medical formulation. The storage device has multiple inserts, each insert containing a single dose of the formulation. Each insert is located in a separate and sealed cavity. The cavities can be individually opened for dispensing the respective dose from the respective insert by movement of the respective insert through the seal, so as to break the seal only at one side of the outlet opening so that the seal is pivoted mainly to an opposite side of the outlet opening by the movement of the insert for minimizing potential interference by the opened seal with flowing of the formulation from the receptacle toward the mouthpiece.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to a dispensing device for dispensing apreferably medical formulation, in particular containing or consistingof a drug or mixture of drugs to a storage device for a preferablymedical formulation, in particular containing or consisting of a drug ormixture of drugs, and to a method for opening such a storage device.

2. Description of Related Art

Drugs delivered through dispensing devices, in particular inhalers, areintended to optimally target specific sites in the pulmonary system.These sites include the nasal passages, the throat, and variouslocations within the lungs, such as the bronchi, bronchioles andalveolar regions. The ability to deliver drugs to a target area dependsinter alia on the aerodynamic sizes of the particles or droplets. Ascurrently believed to be understood, particles having an aerodynamicdiameter of less than 2 micrometer are considered to be potentiallyoptimal for deposition in the alveolar region of the lung. Particlesthat have an aerodynamic diameter of between 2 and approximately 5micrometer may be more suitable for delivery to the bronchiole orbronchi regions. Particles with an aerodynamic size range greater than 6micrometer, and more preferably 10 micrometer, are typically suitablefor delivery to the laryngeal region, throat or nasal passages.

In most cases, it is desired to achieve a high inhalable fraction and ahigh delivery efficiency, i.e., the fraction of the initial dose of drugthat reaches the desired region, in particular, in the lung. Thisdepends on various factors, in particular, on the characteristics of thegenerated spray plume, such as propagation velocity of the plume,particle size and its distribution, fraction of small particles,fraction of gas or the like.

The present invention relates to the dispensing of a preferably medicalformulation. The term “formulation” relates in particular to powder, butmay include or relate to liquid as well. Consequently, the fine“particles” may be either solid or liquid. The term “liquid” has to beunderstood preferably in a broad sense covering inter alia solutions,suspensions, suslutions, mixtures thereof or the like. Moreparticularly, the present invention relates to the dispensing offormulations for inhalation, such as medical formulations containing orconsisting of at least one drug.

In the following, the description will focus mainly on powderformulations. However, the same applies for liquid formulations.

In particular, the present invention is concerned with dry powderinhalers for the delivery of drugs to the lungs. Many dry powderinhalers are on the market or have been proposed. There are two maintypes, namely the passive ones and the active ones. In passive inhalersall the energy required for de-agglomerating the powder and transferringthe powder to the lungs is provided by the breathing of a user, i.e.,the patient. In active inhalers, there is an additional source of energyto help to transfer and de-agglomerate the powder.

Most powder inhalers are of the passive type where the powder is inhaledby the patient without the aid of an additional energy source. Theproblem with passive inhalers is that the inhalable fraction, or theproportion of powder that actually enters the lungs, is largelydependent on the breathing of the patient. The transfer andde-agglomeration of the powder and hence the inhalable fraction is afunction of the flow rate of inhaled air through the device and,therefore, varies greatly from patient to patient.

Dry powder inhalers are subdivided into single dose and multi-dosedevices or inhalers. Multi-dose inhalers are further subdivided intopre-metered types where the doses are stored individually and intometering inhalers where each powder dose is metered in the device.

Multi dose pre-metered inhalers have the advantage that the single dosesare metered under strict factory conditions and the powder can quiteeasily be isolated from the atmosphere. In many applications the activedrug powder is mixed with a carrier such as lactose. The lactose and/oractive drug(s) tend to absorb humidity from the atmosphere, which makesthem stick together and difficult to transfer and de-agglomerate.

The present invention relates, in particular, to an active, gas(preferably air) powered, pre-metered multi-dose dispensing device fordispensing a formulation containing or consisting of a drug, such as adry powder inhaler.

U.S. Pat. No. 4,627,432 discloses a device for administering medicamentsto patients, namely an inhaler. The inhaler comprises a disk-likeblister pack having a plurality of blister pockets arranged in a circle.Each blister pocket contains a dose of the powder. A plunger can open ablister pocket. When a blister is opened, the medicament can bewithdrawn by a patient inhaling through a mouthpiece.

International Patent Application Publication WO 2005/002654 A2 disclosesa passive device for dispensing individual doses of powder. The dosesare contained in respective pockets of a disc-shaped carrier and openedby outwardly rupturing a lidding foil in axial direction by means ofpressure on an opposite side surface. The pockets are moveable in anaxial direction into an airstream generated by breathing of a patientfor dispensing a dose of powder from the pocket. The device providesindividual respective deaggregation flow paths for each pocket, splitairstreams allowing improved entrainment of powder, a cam mechanism foroutwardly rupturing the pockets, an indexing mechanism linked to the cammechanism, and a dose counter.

It is difficult to empty the respective pocket completely during adispensing operation. Incomplete emptying results in decreased deliveryefficiency. Some powder may be lost in the inhaler and not dispensedbecause the known solutions require relatively long paths for the powderuntil the powder reaches a nozzle and is actually dispensed. This mightreduce the delivery efficiency further. In addition, de-agglomeration ofthe powder is difficult.

International Patent Application Publication WO 2006/037636 A2 disclosesan active dispensing device with an air pump for dispensing powderseparately from storage chambers in a common carrier. Preferably, anindividual deaggregation and outlet duct having a flat cross-section isassociated to each storage chamber.

International Patent Application Publication WO 2007/018568 A1 disclosesan inhalation device with multiple separate and pre-metered doses of aformulation in receptacles. According to one embodiment, the sealedreceptacles comprise inserts containing the doses of the formulation.The inserts may comprise cutting edges at opposite sides of an outletopening. The outlet opening is opened by movement of the insert due tocentrifugal forces acting on the insert so that the cutting edges canpierce the seal to open it. It is problematic that the seal is opened inan undefined manner and/or that the opened seal can still interfere withan outlet of the insert which may negatively influrance the discharge ofthe formulation and/or characteristics of the spray during discharge.

SUMMARY OF THE INVENTION

A primary object of the present invention is to provide an improveddispensing device and storage device for dispensing a preferably medicalformulation, and to a method for opening a storage device, inparticular, whereby a compact construction, easy handling or operation,a high delivery efficiency and/or desired spray plume characteristicscan be achieved.

The above object is achieved by a dispensing device and a methodaccording to the present invention as described herein.

According to the present invention, the storage device comprises insertsthat are moveable within respective cavities or receptacles. Each insertcomprises an opening means in order to facilitate opening of anassociated seal by movement of the respective insert through a sealedoutlet opening of the cavity or receptacle. The opening means arelocated at or adjacent to the outlet opening and only at one side of theinsert, cavity or opening so that the seal is pivoted or bent mainly tothe opposite or other side by the movement of the insert through theopening or seal. This leads to a defined opening, and in particular,prevents any potential interference by the opened seal with an outlet ofthe insert. Thus, a simple and compact construction can be achieved. Inparticular, the necessary outlet stroke of the insert can be minimized.Further, a high delivery efficiency and/or desired spray plumecharacteristics can be achieved due to the defined opening of the seal.

According to one preferred aspect of the present invention, an actuator,in particular a grip, of the dispensing device is radially movable oroperable to rotate the storage device to the next receptacle and/or toradially move the connecting element in order to individually open therespective receptacle and/or to connect a gas supply or pump to therespective receptacle and/or to push an insert out of the respectivereceptacle. This allows a compact construction and/or easy handling oroperation.

Another preferred aspect of the present invention is that the dispensingdevice comprises a means for preventing a backstroke of the connectingelement during dispensing. This allows easy handling or operation andensures high delivery efficiency and/or desired spray plumecharacteristics.

According to a further preferred aspect of the present invention, thedispensing and storage device comprise means for aligning the connectingelement and the respective receptacle, wherein said means compriseguiding portions formed at or by the storage device and/or thereceptacles. This ensures correct alignment and, thus, the desireddispensing with high delivery efficiency and/or desired spray plumecharacteristics, wherein compact construction and easy handling oroperation are possible.

According to another preferred aspect of the present invention, thedispensing device or storage device comprises means for limiting themovement of the inserts. This allows a compact and simple constructionand easy handling or operation.

According to a further preferred aspect of the present invention, thedispensing device comprises means for reinserting the inserts into therespective receptacles after use. This allows a compact and simpleconstruction and/or easy handling or operation.

According to another further aspect of the present invention, thestorage device comprises a common carrier, wherein the receptacles areseparate parts mounted on the carrier by clipping, snapping, pressingand/or clamping. This allows a compact and simple construction and, inparticular, an optimized filling of the receptacles, preferably ofinserts of the receptacles, with the dosed formulation.

According to another preferred aspect of the present invention, thestorage device comprises an empty or hollow or dummy receptacle intowhich the connecting element can engage in a state before first use orwhen mounting the dispensing device. This allows a compact and simpleconstruction and, in particular, facilitates mounting of the dispensingdevice.

According to a further preferred aspect of the present invention, thedispensing device comprises multiple, in particular three, lifespanblocking means. In particular, the blocking means are at least partlyformed by the storage device, preferably by a common carrier supportingmultiple receptacles of the storage device. This allows a compact andsimple construction and/or easy and secure handling and operation.

According to a further preferred aspect of the present invention, thedispensing device comprises detection means for detecting inhalation orbreathing in and/or trigger means for triggering dispensing of therespective dose by means of pressurized gas. This allows easy and simplehandling and operation.

Preferably, each insert comprises at least one channel and/or nozzlearrangement in order to directly form the spray during use. Thus, thespray is generated by the respective insert when pressurized gas issupplied. This makes it possible to respectively generate sprays withthe desired spray plume characteristics with high accuracy.

Further aspects, advantages and features of the present invention willbe apparent from the following detailed description of preferredembodiments in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic sectional view of a dispensing device with astorage device according to one embodiment of the present inventionduring dispensing;

FIG. 2 is a schematic section of the storage device with an insert;

FIG. 3 is a schematic sectional view of the insert;

FIG. 4 is a schematic sectional view of the insert taken along lineIV-IV of FIG. 3;

FIG. 5 is a schematic sectional view of another insert;

FIG. 6 is a schematic sectional view similar to FIG. 4 of the insert,but taken along line VI-VI of FIG. 5 and with a carrier and an insertedpiercing element;

FIG. 7 is a schematic perspective view of a dispensing device accordingto a further embodiment of the present invention;

FIG. 8 is a schematic view of inner components of the dispensing deviceaccording to FIG. 7 with retracted air assembly;

FIG. 9 is a schematic view of inner components of the dispensing deviceaccording to FIG. 7 with advanced air assembly in an activated state;

FIG. 10 is a schematic view of inner components of the dispensing deviceaccording to FIG. 7 with advanced air assembly after dispensing;

FIG. 11 is a schematic view of a receptacle of a storage device;

FIG. 12 is a schematic view of a carrier of the storage device;

FIG. 13 is a partial enlarged view of the carrier according to FIG. 12;

FIG. 14 is another partial enlarged view of the carrier according toFIG. 12;

FIG. 15 is a schematic perspective view of a needle holder of the airassembly;

FIG. 16 is a schematic, partially sectional perspective view of thedispensing device according to FIG. 7 with a pulled grip; and

FIG. 17 is a schematic view of a half of the housing of the dispensingdevice according to FIG. 7.

DETAILED DESCRIPTION OF THE INVENTION

In the figures, the same reference signs are used for the same orsimilar parts and components, wherein the same or similar features,aspects and/or advantages are achieved in the different embodiments,even if a repetition of the respective description is omitted.

FIG. 1 shows in a schematic sectional view—for illustration purposes notin scale—a dispensing device 1 according to the present invention. Thedispensing device 1 is preferably an active device, in particular, gaspowered. Preferably, the dispensing device 1 is an oral or nasalinhaler, in particular a dry powder inhaler, for a user, respectivelythe patient (not shown).

Preferably, the dispensing device 1 is portable and/or hand-held.

The dispensing device 1 may be used for dispensing any formulation 2 asdefined in the introductory part of the description. In particular, amedical formulation 2 or a formulation 2 for inhalation will be used.The formulation 2 preferably contains or consists of at least one drug.When the formulation 2 is dispensed, a spray 3 is generated as indicatedin FIG. 1. The spray 3 includes or consists of fine particles (solidand/or liquid) and preferably has the desired spray plumecharacteristics.

The formulation 2 may be a liquid, in particular a solution, asuspension or any mixture thereof, i.e. a so-called suslution.Preferably, when different drugs are dispensed simultaneously, asuslution may be used. The principle of the suslution is based on thatdifferent drugs may be combined in one formulation simultaneously as asolution and as a suspension. In this respect, reference is made to EP 1087 750 A1, which is incorporated herein as additional disclosure inthis respect.

Preferably, the formulation 2 is a powder. The powder may be a pure drugor a mixture of at least two drugs or any other mixture of at least onedrug. In addition, the powder may contain at least one other material,in particular a drug carrier such as lactose. In the following, thedescription focuses on powder as formulation 2. However, this applies ina similar manner if a liquid formulation 2 is used.

Preferably the mean diameter of the powder particles is about 2 to 7micrometer, in particular 6 micrometer or less. This applies inparticular if the powder does not contain any drug carrier such aslactose.

If the powder contains a drug carrier, such as lactose, and at least onedrug, the powder 2 may have a particle size of 20 to 300 micrometer, inparticular about 30 to 60 micrometer. However, the de-agglomeration,which will be described later in more detail, may result even in thiscase in a spray 3 with a smaller particle size, e.g. of about 10micrometer or less. In particular, the drug may be separated from thedrug carrier during de-agglomeration so that primarily the drug will beinhaled due to its small particle size of about 2 to 6 micrometer andthe larger drug carrier will be swallowed when using the dispensingdevice as an inhaler. Alternatively or additionally, breaking or openingof the drug carrier is possible during de-agglomeration.

The diameters mentioned above and below may be understood as mass mediumaerodynamic diameters and/or may apply to the particle size or afraction of the particles of the spray 3.

Preferably, the formulation 2 is premetered in separate or individualdoses, which can be discharged one after the other by the dispensingdevice 1, in particular for inhalation.

The dispensing device 1 is adapted to receive or comprises a storagedevice 4 for storing preferably multiple and pre-metered doses of theformulation 2. The storage device 4 may be integrated into thedispensing device 1 or form part of the dispensing device 1.Alternatively, the storage device 4 may be a separate part that can beinserted or connected with the dispensing device 1 and optionallyreplaced.

FIG. 2 shows a schematic cross-section of the preferably ring-likestorage device 4.

The storage device 4 preferably comprises a carrier 5 and at least oneinsert 6, preferably multiple inserts 6. In particular, the carrier 5may comprise or support 20 to 100 inserts, but preferably 30 to 60inserts 6. Each insert 6 preferably contains one pre-metered dose of theformulation 2. However, each insert 6 may also contain more than oneformulation 2, i.e., different formulations 2. Additionally oralternatively, different inserts 6 may contain different formulations.In the context of the present invention, “different” means, inparticular, that the formulations 2 differ in at least one of thecomposition, the drug, the dose or amount, the concentration, andconsistency of the formulation 2, e.g., liquid or dry powder.

The storage device 4 or carrier 5 preferably comprises multiple cavities7 or receptacles for receiving or containing the inserts 6. Inparticular, each insert 6 is located in a separate cavity 7. Preferably,the cavities 7 are separate from each other, and in particular, aresealed relative to each other.

In the present embodiment, each cavity 7 comprises at least one opening8, in particular two, preferably opposed openings 8 (here, at theradially inner and outer circumference or periphery).

The cavities 7 or its openings 8 are covered by respective covers orseals 9 which are preferably formed by heat-sealed foils on oppositesides of the respective cavity 7 or the carrier 5. In the presentembodiment, the seal 9 is, in particular, a metallic foil, such asaluminum foil, plastic foil, a multi-layer arrangement or the like. Theseals 9 preferably protect the inserts 6 and/or formulation 2 againsthumidity, dirt, moisture and/or the like. The seals 9 are respectivelyresistant and/or impermeable, in particular, gas-tight.

In this preferred embodiment, the storage device 4 or carrier 5 isring-shaped and the cavities 7 extend at least substantially in a radialdirection. The cavities 7 are distributed around the perimeter of oralong the storage device 4 or carrier 5, preferably equally spacedrelative to the adjacent cavities 7.

In the present embodiment, the storage device 4/carrier 5 is preferablyrotatable around axis “A” shown in FIG. 1. In particular, the dispensingdevice 1 can be opened and the storage device 4/carrier 5 can beinserted or replaced.

The carrier 5 may be a molded element, a ring, a strip, a cartridge, ablister or a container. Preferably, the storage device 4 or carrier 5 isrigid or at least essentially stiff.

Preferably, the carrier 5 is made of foil, plastic, ceramic and/or acomposite material, in particular, a thermoplastic or thermoplasticelastomer.

Each cavity 7 or receptacle preferably forms a guide for the associatedinsert 6, in particular, so that the insert 6 is moveable in at leastone direction and/or at least partially out of the cavity 7 orreceptacle.

FIG. 1 shows a situation, where the insert 6 on the right side hasalready been pushed partially out of its associated cavity 7 and/or theouter opening 8 and/or through the respective seal 9 of its associatedcavity 7 for opening the seal 9. The insert 6 shown on the left side ofFIG. 1 is still within its closed and sealed cavity 7.

Each insert 6 is preferably produced filled with the respective dose offormulation 2 separately from the storage device 4 or carrier 5 and,then, inserted into its respective cavity 7 or receptacle.

Preferably, each insert 6 is molded and/or made of foil, plastic,ceramic and/or composite material, in particular, of thermoplastic or athermoplastic elastomer, and for seals, of elastomers or silicone.

According to a preferred embodiment, the carrier 5 and/or the inserts 6are made of at least one of the following materials or any mixture orblend thereof:

ABS (acrylonitril-butadiene-styrene copolymer); SAN(styrene-acrylonitril-copolymer); PBT (polybutylene terephthalate); PC(polycarbonate); CA (cellulosic acetate); EVA (ethylene vinylacetatecopolymer); PA (polyamide); PE (polyethylene); PP (polypropylene); PMMA(polymethylmethacrylate); POM (polyoxymethylene, polyacetal); PPS(polyphenylene sulfide); PS (polystyrene); PBTP (polybutyleneterephthalate); TPU (thermoplastic polyurethane); blend of PC and PBTP;blend of PC and ABS; LCP (liquid crystal polymers); PHCS (polypyrrolorpolythiophene); PPA (polyphthalamide); PSU (polysulfone); PTFE(polytetrafluorethylene); PUR (polyurethane); SB (styrene-butadienecopolymer); PIB (polyisobutylene); PAN (peroxyacylnitrate); PET(polyethylene terephthalate); AMMA (acrylonitril-methymethacrylatcopolymer); PAR (polyarylate); PEEK (polyetheretherketone); COC(cycloolefine copolymer).

Each insert 6 may form a preferably block-like unit and/or be rigid.Alternatively, the inserts 6 may be flexible. In particular, each insert6 may be a unitary unit or formed of multiple elements. In particular,the insert 6 forms a unitary component or is made of one piece. Eachinsert 6 may be a molded element, a cartridge, a blister, a capsule, acontainer or the like.

In the following, a preferred construction of one insert 6 is explained.Preferably, all inserts 6 are identical. However, it is also possiblethat the all or some of the inserts 6 are different. For example, two ormore groups of different inserts 6 can be provided. It is possible thatone group has a different dosage or a different formulation 2 than theother group. For example, the inserts 6 of the different groups could bearranged alternately one after the other so that a patient or user mayuse, for example, each morning an insert 6 of one group and each eveningan insert 6 of the other group.

Each insert 6 preferably comprises a storage chamber 10 for a singledose of the formulation 2. The schematic sectional view according toFIGS. 2 & 3 and the schematic sectional view according to FIG. 4, whichis a view along line IV-IV of FIG. 3, show one preferred embodiment ofthe insert 6. The insert 6 comprises a storage chamber 10 for theformulation 2. In the present embodiment, the storage chamber 10 ispreferably formed in a molded base member 11 of the insert 6.

The insert 6/base member 11 further comprises a duct 12 or the like fordeagglomerating and/or discharging the formulation 2 during thedispensing operation. The formulation 2 is dispensed through the duct 12during the dispensing operation, in particular for de-agglomerating thepowder and/or forming the spray 3.

Preferably, the duct 12 is flat and/or rectangular in cross section. Inparticular, the cross section corresponds to a hydraulic diameter ofless than 1 mm. In particular, the duct 12 is designed as described inInternational Patent Application Publication WO 2006/037636 A2, which isincorporated herein by reference.

According to another (unillustrated) embodiment, the duct 12 can also beused as a reservoir (storage chamber 10) for the formulation 2. In thiscase, the separate storage chamber 10 is not required. Then, the duct 12is designed to enable sufficient mixing of the gas with the formulation2 and sufficient de-agglomeration of the powder formulation 2.

Preferably, the spray 3 having its desired spray characteristics isdirectly ejected or discharged from the insert 6/duct 12.

As noted above, the insert 6 is formed as unitary component or is madeof one piece. The insert 6 or duct 12 can comprise a nozzle arrangement13, preferably, at an outlet 15 or end of duct 12 or formed by duct 12,as shown in the schematic longitudinal sectional view of anotherembodiment according to FIG. 5.

Preferably, the storage chamber 10 and/or the duct 12/nozzle 13 isformed by or in the base member 11, in particular, by a recess, grooveor the like in the base member 11 and by an associated cover member 14as shown in FIG. 4. In particular, the duct 12 forms a channel from thestorage chamber 10 to the outlet 15 of the insert 6, in particular, fordirectly discharging or dispensing the formulation 2 as spray 3 as shownin FIG. 1. Preferably, the base member 11 is molded and/or rigid.Preferably, the cover member 14 is rigid and/or is welded to the basemember 11.

It is noted that the inserts 6 may be or are preferably open, i.e., notsealed, in particular, at their respective outlet 15 only sinceexperiments have shown that sealing of the carrier 5/the cavity 7 issufficient. The duct 12/nozzle arrangement 13 is preferably so small incross section or is provided with a bursting element or any othersuitable means that insures that the formulation 2 is not discharged,even with an opened seal 9 and/or during strong shaking of thedispensing device 1/storage device 4, but rather is dischareged onlywhen gas (air) is forced through the insert 6 and duct 12.

The storage device 4 may comprise only one insert 6 with one storagechamber 10 for a single dose or can be provided with multiple storagechambers 10 with different formulations 2. In the preferred embodiment,each insert 6 is for a single dose and/or single use only, but thestorage device 4 preferably comprises multiple inserts 6 and, thus,contains multiple doses of the formulation 2, which can be dispensedsubsequently.

Further, the inserts 6 and cavities 7 are preferably adapted to eachother such that the seals 9 contact end faces of the inserts 6, andthus, cover the outlets 15. This may further prevent any formulation 2from dissipating through the duct 12/outlet 15 before the desireddispensing. In order to increase the seal or cover effect of seal 9, theinserts 6 may be slightly longer than the cavities 7 and/or protrude attheir outlet side and/or be pressed with their outlets 15 against theseals 9 or vice versa.

Preferably, the nozzle arrangement 13 forms a means for slowing down thevelocity as shown in the embodiment of FIG. 5. This means forms, here, amultiple jet impinging means. The means forms multiple—at least two—jetsP which impinge, i.e., hit, each other, as indicated in FIG. 5. In thisembodiment, the duct 12 divides into two sections 12 a, 12 b that aredesigned such that the openings or outlets 15 are angled toward eachother so that the jets P ejected from the sections 12 a, 12 b impinge.For example, a flow divider 11 a or any other guiding means can belocated in the flow path to form the at least two sections and/or lastsections 12 a, 12 b of the duct 12 as shown in FIG. 5.

The embodiment according to FIG. 5 is also suitable for impinging morethan two jets P. For example, it is possible to have similararrangements in the cross sectional planes perpendicular to the drawingplane resulting in four outlet directions and jets P arranged on thesurface of a conus. However, multiple other arrangements with similareffects are possible.

The impinging angle W between the jets P is between 30 and 180 degrees,preferably at least 90 degrees for powder, in particular, about 90 to150 degrees.

The impinging of the jets P results in a decrease of the velocity of thespray 3 and/or in a de-agglomeration of the powder or forming of smalldroplets and/or in separation of drug particles from a carrier and/or inbetter focusing of the spray 3. These effects depend on the impingingangle W. A larger impinging angle W tends to result in better effects.In contrast to liquid jets, an impinging angle W of 90 degrees or moreis possible and preferred for powder.

Alternatively, the nozzle 13 or any other suitable nozzle arrangementcould be used instead of or in any other combination with duct 12.

FIG. 6 shows a schematic sectional view of the insert 6 taken along lineVI-VI of FIG. 5, wherein the insert 6 is housed in its cavity 7/storagedevice 4, but has already moved somewhat outward of one opening 8.

The insert 6 preferably has an inlet for supplying preferablypressurized gas into the storage chamber 10 to force the formulation 2through the duct 12/nozzle arrangement 13 and directly generate thedescribed spray 3. In the present embodiment, the inlet is preferablyformed by a weak or thinned portion and/or is designed as a preferablytube-like recess 16 or blind bore formed in the base member 11.Preferably, the recess 16 is not directly connected to the storagechamber 10, but is separated by a seal or an intermediate or thinnedwall or the like. This wall can be penetrated, e.g., by a piercingelement 17, such as a needle as shown schematically in FIG. 6 or by anyother suitable opening, connecting and/or supply means, in particular,when the respective insert 6 is connected to a gas supply as explainedin the following. Preferably, the piercing element 17 is a hollow needlewith a solid or closed tip 17 a and a side opening 17 b adjacent the tip17 a for supplying the pressurized air into the insert 6/storage chamber10.

In the present invention, the expression “piercing element 17”preferably covers also all other suitable types of means for openingand/or connecting the storage device 4, the carrier 5, a cavity 7 and/oran insert 6 and/or for directly or indirectly supplying gas to an insert6 or its respective storage chamber 10.

It is noted that the cross sections of the inserts 6 and the cavities 7are preferably polygonal, in particular, rectangular or that otherguiding means are preferably provided, in order to avoid that theinserts 6 rotate within the cavities 7. However, if the inserts 6 arerotatably symmetrical with respect to the recess 16 or any otherconnection/inlet for gas supply and with respect to its outlet 15, theinserts 6 may also be cylindrical and/or can rotate within the cavities7. This may facilitate insertion of the inserts 6 into the cavities 7during production.

The duct 12 is preferably at least tangentially connected to the storagechamber 10 as shown in FIGS. 3 & 5. Preferably, the duct 12 is connectedat one axial end of the preferably cylindrical chamber 10, and the gasinlet (recess 16/piercing element 17) is connected or connectable to theother axial end of the chamber 10 as indicated in FIG. 6. In particular,the gas inlet is connected also tangentially to the storage chamber 10,such that swirls are generated by the entering gas with a swirldirection supporting discharge of the mixture of gas and formulation 2through the duct 12, which connects tangentially to the rotationaldirection of the swirl.

The dispensing device 1 uses preferably pressurized gas, in particularair, to force the formulation 2 through the duct 12/nozzle arrangement13 to de-agglomerate the powder and/or to generate the spray 3 with finepowder particles. Preferably, the dispensing device 1 comprises a meansfor providing pressurized gas, in the present embodiment, an air pump18, as indicated in FIG. 1, which can preferably be actuated or operatedmanually, e.g., as indicated, by a handle or actuator 19 and/or by aspring means as shown later in another embodiment. In particular, theair pump 18 comprises or is formed by a bellows. But, it could also be apiston-cylinder-arrangement. Instead of the air pump 18, the means forproviding pressurized gas can be, e.g., a capsule, container or the likecontaining pressurized or liquefied gas for powering the dispensingdevice 1, i.e., dispensing the formulation 2 as desired. Therefore, theterm “means for pressurizing gas” is to understood in a broad sense tocover these and similar alternatives to the pump 18 as well.

The means for providing pressurized gas/air pump 18 may provide a gaspressure of less than 300 kPa, in particular, about 50 to 200 kPa. Thisis preferably sufficient for operating the dispensing device 1. Ifliquefied gas or a container with pressurized gas is used, the gaspressures might range from 100 kPa to about 700 kPa. Then, the pressuremay be reduced or throttled to the preferred pressure range beforesupplying the gas to the storage device 4, in particular, the storagechamber 10 of the respective insert 6.

Preferably, all pressure values mentioned in the present description aregauge pressures, i.e., pressure differences. All pressure values relateto the pressure in a gas storage, such as a container with pressurizedor liquefied gas or provided by air pump 18 or relate to the pressuresacting in the chamber 10 and/or in the duct 12.

FIG. 1 shows that the dispensing device 1 preferably comprises amechanism 20 for individually opening the cavities 7, for individuallymoving the inserts 6, preferably radially (here outwardly) and/orthrough an associated opening 8 and/or seal 9, and/or for individuallyconnecting the inserts 6 to the gas supply, in particular to the airpump 18. The mechanism 20 comprises preferably the piercing element 17and/or any other suitable connecting or actuation element.

In particular, in a first operation phase the piercing element 17penetrates the seal 9, and then, is inserted into the recess 16 andthrough the intermediate end or weakened wall into the storage chamber10, and thus, connects the respective insert 6 to the gas supply.Before, simultaneously or afterwards, e.g., during the further movement,the mechanism 20 pushes the insert 6 through the other or outer opening8 and through the respective seal 9 at least partially out of its cavity7. Preferably, the mechanism 20 acts directly on the respective insert 6to cause its movement. Here, the piercing element 17 is preferablyprovided with a shoulder or abutment or sleeve 21 (shown schematicallyin FIG. 6) abutting at the insert 6 to positively cause the desiredmovement of the insert 6 when moving the mechanism 20/piercing element17. The final situation is shown in FIG. 1 on the right side and in FIG.6 with protruding insert 6.

It is noted that any other driving mechanism can be used to move theinsert 6 to open one opening 8/one seal 9/respective outlet 15 or theinsert 6 itself. In particular, it is possible to realize the preferredpushing of the insert 6 through the seal 9 independently of theconnecting or piercing of the insert 6.

In order to facilitate opening of the respective seal 9, the insert 6comprises preferably an opening means, in particular a tip portion 11 b,and/or is tapered at its outlet end and/or at the outlet opening 8 ofthe respective cavity 7 or receptacle. In particular, the insert 6 orits base 11 or the opening means comprises an inclined or taperedportion 11 c—preferably at least or only one preferably flat side of theinsert 6 or base 11—so that the insert 6/base 11 is inclined or taperedtowards the outlet 15, as shown schematically in FIGS. 4 & 6. Thus, itis possible to form a tip or tip portion 11 b, which forms a front facewith reduced or minimal surface. It is even possible to form a cuttingedge at the outlet end and/or by the shown tip portion 11 b or any otheredge of the insert 6.

Alternatively or additionally, it is possible to form or provide anyother suitable cutting element as opening means at the insert 6, inparticular at its outlet end.

In particular, the stroke or outward movement of the insert 6 is adaptedand preferably sufficiently long that the desired opening of the seal 9is ensured, and in particular, that the broken, cut and/or rupturedparts of the opened seal 9 cannot hinder or cover or interfere with theoutlet 15 of the insert 6. In the present embodiment, the seal 9 issubstantially ruptured or cut at a side of the opening 8 where theopening means, a cutting edge or the tip portion 11 b of the insert 6 islocated. The short rest of the seal 9 mounted on this side of theopening 8 cannot interfere with the outlet 15 of the protruding insert 6because it is preferably shorter than the outward stroke of the insert6. The longer part of the seal 9 connected to the opposite or other sideof the opening 8 will be bent or pivoted away by the insert 6, inparticular to this other side of the insert 6, cavity 7 or opening 8.This allows the outward stroke of the insert 6 to be minimized whileensuring a defined opening of the seal and preventing any interferenceof the ruptured or cut seal 9 with the spray 3 and/or outlet 15 of theinsert 6.

In the present embodiment, the opening and/or cutting of the seal 9takes place at a side or adjacent to an edge of the preferablyrectangular opening 8 when the respective insert 6 is moved outward ofits cavity 7 for activating and later dispensing. The opening means, tipportion 11 b, cutting element or the like is located at one side of theinsert 6, and in particular, adjacent to one side of its cavity 7 andopening 8 so that the mentioned opening of the respective seal 9 occursas described when the insert 6 is moved outward. In other words, thelocation of the opening or cutting means may be, and in particular, isused to ensure or cause a desired opening pattern and/or location of therespective seal, in particular at one side and/or adjacent to one edgeof the opening 8. However, other opening locations can be chosen. Forexample, it is also possible to open the respective seal 9 in thecenter. Additionally or alternatively, the insert 6 may be adapted—inparticular, by provision of two or more opening or cutting means—to openor rupture or cut the respective seal 9 at multiple regions subsequentlyor simultaneously at preferably only one side of the opening 8 so that,as in the case above, the seal 9 is bent or pivoted essentially to theopposite or other side of insert 6, cavity 7 or opening 8.

In the present embodiment, the insert 6 is preferably moveable radiallyand/or outwardly and/or away from the airpump 18 and/or in itslongitudinal direction and/or in the main discharge direction and/or inthe main extension of the mouthpiece 24. However, other movements arealso possible. In the present case, only a translational movement isproduced. However, a rotational or pivotal movement can be producedadditionally or alternatively or superposed.

Preferably, the storage device 4, the carrier 5 and/or the cavities 7comprise means for limiting the possible or maximum movement of theinserts 6. Preferably, this means stops the insert(s) 6 by form-fit. Inthe present embodiment, the means comprise stops 22, e.g., shoulders,protrusions or the like, which interact with a respective abutment, suchas a shoulder 23, of the respective insert 6 so that the insert 6 islimited in its movement out of the respective cavity 7 as shownschematically in FIG. 6 where the shoulder 23 abuts the respective stop22 and, thus, prohibits any further outward movement of the insert 6.However, it is noted that any other technical solution having the sameeffect can also be used.

For dispensing, the gas is supplied under pressure to the storagechamber 10 via the piercing element 17 or any other suitable supplyelement.

The gas (air) generates a respective flow in the storage chamber 10 tomix gas and powder and to force the dose through the duct 12.

The powder will be discharged—in particular forced through the duct12—with a comparatively low gas pressure (preferably less than 300 kPa,in particular about 50 to 200 kPa). This low gas pressure, which issignificantly lower than the gas pressures in the prior dispensingdevices, enables a respectively low discharge velocity and, therefore, aslow spray 3 with slow propagation velocity.

Preferably, the storage chamber 10 forms a mixing chamber for mixing thegas with the powder. The chamber 10 is preferably designed such that thegas can generate swirls or eddies for better mixing the powder with thegas. Preferably, the chamber 10 is substantially circular in crosssection, in particular cylindrical. However, other shapes are alsopossible.

Further, the chamber 10 is formed with no sharp edges, corners or thelike, but has a smooth contour so that the gas can sweep all chambersurfaces to prevent powder accumulating on said surfaces and to ensureor allow complete discharge of the powder. In particular, the gas inletformed by the piercing element 17 or any other supply element is locatedopposite to the outlet, i.e., duct 12 and/or nozzle 13, with regard tothe axial or outlet direction.

During the dispensing operation, the spray 3 is preferably directly oronly generated by the respective insert 6 or its duct 12/nozzlearrangement 13 and output into a mouthpiece 24 of the dispensing device1 as shown in FIG. 1 for inhalation by a patient or user (not shown).

After dispensing one dose or before or for dispensing the next dose, thepiercing element 17 will be withdrawn from the connected insert 6.Preferably, the respective insert 6 is also retracted or pushed backinto its cavity 7.

Then, the carrier 5 will be indexed one step further or to the nextinsert 6, in particular rotated by means of an indexing or transportmechanism (not shown). This mechanism is preferably operated byactuating actuator 19 or any other actuator, by opening a cap or coverof the dispensing device 1 or the like, as already mentioned.

It is noted, that the present invention, in particular the dispensingdevice 1 and/or the storage device 4, can be used for dispensing onedrug, a blend of drugs or at least two or three separate drugs. In thelatter case, the separate drugs are stored in separate storage chambers10, and during the dispensing operation, the drugs are mixed with thegas either in a common mixing chamber or in their respective storagechambers 10. Further, the separate drugs can be discharged through acommon duct 12 or nozzle arrangement 13 or through separate ducts 12 ornozzles 13. In the latter case, the separate drugs will be mixed afterleaving the separate ducts 12/nozzles 13 or in the mouthpiece 24 or inany other suitable (additional) mixing chamber. It is also possible tomix the separate drugs by impinging jets of the separate drugs. Fordispensing the separate drugs, it is preferred to use a common gassupply or means for pressurizing gas such as air pump 18.

Preferably, the spray 3 has a mean velocity (taken 20 cm from the outlet15 or mouthpiece 24) of less than 2 m/s, in particular less than 1 m/s.Preferably, the mean duration of the spray 3 is at least 0.2 or 0.3 s,and in particular, about 0.5 to 25.

In the preferred embodiment according to FIG. 1, the cavities 7 areorientated in a tangential or radial direction of the storage device 4or carrier 5. Consequently, the inserts 6 can be individually moved in atangential or radial direction, in particular, outwardly, in order toopen the respective outer seal 9 for dispensing the respective dose ofthe formulation 2 as indicated in FIG. 1. Accordingly, the mechanism 20preferably operates in a radial direction for connecting the inserts 6individually to a gas supply and for pushing the inserts 6 individuallyat least partially out of the respective cavity 7 and/or through therespective seal 9. This radial movement allows a very compact design ofthe dispensing device 1, in particular in axial direction.

Preferably, the mouthpiece 24 and the dispensing direction extends in aradial or tangential direction as shown in FIG. 1.

Preferably, the dispensing device 1 comprises a lever or handle (notshown) or the actuator 19 or any other driving or an actuation means forpreferably manual actuation in order to index the carrier 5 one stepfurther, i.e., to the next insert 6, and/or to operate the mechanism 20,preferably to connect the respective insert 6 to the gas supply and/orto move/push the respective insert 6 and/or to open the respective seal9 for dispensing the respective dose of the formulation 2.

It is noted that the dispensing device 1 operates preferably onlymechanically.

According to another embodiment (not shown), the inserts 6 may be formedas capsules or the like without any duct 12, nozzle 13 or the like.Instead, each insert 6 is connected individually to a gas supply and toa common outlet arrangement, such as a duct 12, nozzle 13 or the likefor dispensing the respective dose of the formulation 2.

According to another embodiment, a secondary packaging may be used forpacking and protecting the storage device 4/carrier 5, in particular,for storage purposes before inserting the storage device 4/carrier 5into the dispensing device 1. Additionally the whole device 1 includingthe storage device 4/carrier 5 may be stored in a secondary water vaporproof packaging.

According to a further embodiment, the dispensing devise 1 may be breathactivated, in particular, wherein the formulation 2 is only releasedafter the patient's or user's inhalation rate has reached apredetermined level, preferably by the use of a pressure sensitivemeans, such as a bursting element, membrane or valve, or any othermechanism.

According to another embodiment, the dispensing device 1 may also be apassive inhaler wherein a patient or user (not shown) produces anairflow through the respectively opened insert 6, when breathing in sothat this airflow entrains the formulation 2 and forms the desired spray3 in the mouthpiece 24 for inhalation by the patient/user.

It is noted that the term “dispensing device” is to be understood in abroad sense to include other discharge devices, dispensers or the like,preferably, wherein the formulation 2 or any other fluid is sprayed oratomized only when needed, in particularly discontinuously.

In the following, a further preferred embodiment of the dispensingdevice 1 will be explained with reference to the further drawings. Thefollowing description will focus on relevant differences between thefurther embodiment and the previous embodiments. In particular, theprevious explanations and descriptions apply accordingly and/oradditionally, even if not repeated.

FIG. 7 shows the further embodiment of the dispensing device 1 in aperspective view. The dispensing device 1 comprises a cover 25 forcovering the mouthpiece 24. Preferably, the cover 25 mounted so as topivot for opening or uncovering the mouthpiece 24 as shown. Preferably,the mouthpiece 24 is snapped onto a housing 26 of the dispensing device1.

The dispensing device 1 comprises an actuator 19 at one side of housing26, preferably on the side opposite the mouthpiece 24 and/or oppositethe main spray direction (preferably in radial direction) of thedispensing device 1. The actuator 19 preferably forms a grip or handle.Therefore, the term “grip” will be used in the following.

The grip 19 is preferably moveable in a radial direction for actuatingthe dispensing device 1 as explained later in more detail. Inparticular, the grip 19 can be pulled radially outwardly from theinitial position shown in FIG. 7 and pushed back into its initialposition. These operations are, for convenience, named “pulling” and“pushing,” respectively, in the following. However, it is noted thatthese operational movements could also be realized by any otherdirection or type of movement, such as a non-translational movement.

First of all, the basic principle of the dispensing device 1 will beexplained with reference to FIGS. 8 to 10. FIGS. 8 to 10 show only veryrudimentary schematic views (not to scale) of inner components of thedispensing device 1 for explaining the principle. In particular, thehousing 26 and the grip 19 have been omitted. Further, the storagedevice 4 is shown only in a schematic manner, in particular,incompletely or partially only in FIGS. 9 & 10. In particular, multipledetails, such as seals 9, outlets 15 or the like, have been omitted. Thepreferred construction of the storage device 4 will be explained laterafter explaining the basic functional principle of the presentdispensing device 1.

The dispensing device 1 is an active atomizer or inhaler. The means forpressurizing gas is preferably also constructed as air pump 18. Here,the air pump 18 comprises a bellows 27 as pumping element. However, anyother suitable pumping element could be used.

The dispensing device 1/air pump 18 further comprises an energy orspring store, in particular, a spring 28, for actuating the pumpingelement, i.e., the bellows 27.

The air pump 18 (bellows 27 and spring 28) is preferably radiallymoveable, in particular, in a sliding manner, such as like a sled.Preferably, the air pump 18 is formed as a slider 29 or is supportedthereon. In particular, the air pump 18 and slider 29 will be named the“air assembly” in the following.

Preferably, the air assembly forms or includes the mechanism 20 alreadymentioned with respect to the previous embodiments. For this purpose,the air assembly preferably comprises a needle holder 30 holding thepiercing element/needle 17. The piercing element 17 may be pressedand/or glued or molded into the needle holder 30. Preferably, thebellows 27 is pressed or clamped onto the needle holder 30.

The needle holder 30 may be designed such that it can push therespective inserts 6 outwardly in case that the sleeve 21 or any otherabutment fails.

The needle holder 4 preferably closes or completes the slider frame 31.For example, the needle holder 30 may comprise holds for pins of theslider frame 31, which pins may be heatriveted.

The needle holder 30 is connected to or formed by a slider frame 31,which, in turn, holds the spring 28 and/or moveably guides a tensionelement 32 associated to the bellows 27 and/or spring 28.

In the illustrated embodiment, the bellows 27 is arranged between theneedle holder 30 and the tension element 32. The spring 28 is arrangedbehind the bellows 27, e.g., on the opposite side of the tension element32.

The tension element 32 holds the bellows 27 in order to secure thefilling of the bellows 27 during pulling. Namely, the grip 19 preferablyretracts the tension element 32 during pulling.

The air pump 18 or air assembly is preferably located in the center ofthe dispensing device 1 and/or within the storage device 4 and/orring-like carrier 5 and/or is preferably radially moveable.

FIG. 8 shows the situation after the grip 19 has been pulled out. Thebellows 27 is extended and filled with air. The spring 28 is compressedor tensioned, i.e., the energy store has stored energy. The tensionelement 32 is retracted and locked in its position to hold the spring 28in its compressed state. The air assembly/slider 29 is retracted so thatthe piercing element 27 is retracted from the storage device 4, inparticular, so that the storage device 4 can be indexed or moved, inparticular rotated.

When the grip 19 is pushed back, preferably a transportation operationand a connecting operation will be performed. In the first phase of themovement of the grip 19, a transport mechanism 33 is actuated. Inparticular, a cogwheel 34 of the transport mechanism 33 (shown in FIG.9) at least temporarily meshing with preferably inner teeth 35 of thestorage device 4 or carrier 5 is rotated to move or index the storagedevice 4 by one insert 6 or cavity 7 and/or to the next insert 6 orcavity 7. However, it is noted that this transportation operation couldalso be performed partly or completely during pulling.

Preferably, after termination of the transportation operation, i.e.,during a second phase of pushing, the connecting operation is performed.The air assembly/slider 29 is moved forward and/or radially so that thepiercing element 17 connects to the next/aligned insert 6/cavity 7. Inparticular, the piercing element 17 pierces into the insert 6 to connectto its storage chamber 10. Before, simultaneously and/or subsequently,the insert 6 is moved radially and/or outward and/or pushed through theouter seal 9. As a result, the insert 6/duct 12/outlet 15 is opened.This situation is shown in FIG. 9, wherein the connected and openedinsert 6 is protruding radially outwardly from the storage device 4and/or its cavity 7.

The spring 28 is still biased or compressed. This situation is alsonamed the “activated state.” The dispensing device 1 is ready fordispensing the dose of formulation 2 from the opened/protruding inserts6 shown in FIG. 9.

To initiate delivery (discharge) of the formulation 2 and to generatethe spray 3, a release button 36 (shown in FIG. 7) or any other suitableelement is actuated, in particular, depressed. Thus, the tension element32 or its associated locking means is unlocked (preferably bydepressing/compressing the elastic snap 32 a), and the spring 28 isreleased and compresses the bellows 27. The bellows 27 compresses theair contained therein. Thus, the air is forced through piercing element17 into the connected insert 6. The resulting air stream is forcedthrough the connected insert 6, entraining the powder/formulation 2 ofthe insert 6 and ejecting it as spray 3.

FIG. 10 shows the final state after discharge. The spring 28 hasexpanded and the bellows 27 compressed. The tension element 32 has beenmoved forward to the needle holder 30/piercing element 17. The piercingelement 17 is still connected to the emptied insert 6, and the emptiedinsert 6 is still protruding outward. In this state, the dispensingdevice 1 can be closed and transported. Therefore, this state is alsonamed the “transportation state.”

For the next use, the grip 19 is pulled. In a first phase of themovement, the slider 29/air assembly is retracted together with thepiercing element 17 so that the piercing element 17 is retracted fromthe storage device 4, i.e., out of the cavity 7 of the last insert 6. Ina second phase of movement, which can also happen simultaneously, but ispreferably performed after the slider 29 has stopped, the tensionelement 32 is retracted within the slider 29/slider frame 31 so that thebellows 27 is extended and the spring 28 is compressed or biased untilthe tension element 32 is locked in its retracted position as shown inFIG. 8. During the extension of the bellows 27, air is sucked into thebellows 27, preferably through piercing element 17 and/or optionallythrough a suitable inlet valve (not shown).

It is noted that the release button 36 is preferably lifted only duringthe last phase of pushing the grip 19. Further, the lifted or activatedor primed release button 36 preferably blocks pulling of the grip 19until the release button 36 has been actuated or depressed, i.e., untilthe dispensing device 1 has been triggered. In particular, the releasebutton 36 is tilted during actuation or depressing.

In the following, further details, aspects, features and advantages ofthe present dispensing device 1 and/or of its components will beexplained.

Preferably, the storage device 4 comprises multiple receptacles 37respectively containing only or at least one insert 6, as schematicallyshown in FIGS. 8 to 10. In particular, the receptacles 37 are producedas separate parts that are placed or mounted on the carrier 5. Thereceptacles 37 may be made of the same material as the storage device4/carrier 5, in particular of plastic. Preferably, the receptacles 37are rigid and form a guide for the inserts 6.

Each of the receptacles 37 comprises one or more cavities 7 forreceiving the respective insert(s) 6.

Preferably, the receptacles 37 are provided with the inserts 6 alreadyfilled with the respective dose of formulation 2, and then, mounted onthe comment carrier 5.

The receptacles 37 are preferably sealed separately, i.e., independentlyfrom each other and/or with separate seals 9. The receptacles 37 may besealed before or after placement on the carrier 5. The receptacles 37are preferably sealed on opposite sides and/or on longitudinal endfaces.

FIG. 11 shows in a schematic perspective view one receptacle 37 beforeplacement on the carrier 5. Preferably, the receptacle 37 has anessentially cuboid and/or longitudinal form.

The carrier 5 preferably supports the receptacles 37 fixedly and/or in aform-fit manner. Preferably, the receptacles 37 are snapped on to orinto the carrier 5.

In the present embodiment, the receptacles 37 comprise a protrusion 38for mounting the respective receptacle 37 onto carrier 5. The carrier 5comprises a series of corresponding recesses 39, such as slits orgrooves, as shown in FIGS. 9 & 10. In the embodiment shown in FIG. 11,there are bores for receiving the protrusions 38. In particular, thereceptacles 37 can be snapped, clipped, clamped or pressed with theirprotrusions 38 into the recesses 39 of the carrier 5. For this purpose,the protrusions 38 may comprise a preferably annular portion 38 a withincreased diameter or the like. FIG. 12 shows in a schematic perspectiveview a preferred embodiment of the carrier 5 with bores being providedas recesses 39. Preferably, the recesses and/or protrusions 38 arearranged adjacent to the inner surfaces of the storage device 4, to theinner openings 8 and/or to the side at which piercing or pushing of therespective inserts 6 occurs. However, other mechanical solutions ordesigns are possible to connect the receptacles 37 with the carrier 5.

Alternatively or in additional to the recesses or bores 39, the carrier5 may comprise means for fixing and/or aligning the receptacles 37 onthe carrier 5. In the illustrated embodiment, the carrier 5 preferablycomprises an inner ring wall 40 and/or holding elements 41.

The inner ring wall 40 may form an abutment or stop for the inserts 6which prevent the inserts 6 from being pulled out of their cavities 7when retracting the piercing element 17.

The holding elements 41 are preferably located at the periphery of thecarrier 5 and protrude preferably upwardly so that each receptacle 37can be placed between two adjacent holding elements 41. In particular,the holding elements 41 align the receptacles 37 on the carrier 5correctly and/or radially.

Preferably, the receptacles 37 can be snapped or clamped betweenadjacent holding elements 41. For this purpose, the receptacles 37 maycomprise noses 42 or other suitable engaging means on its respectivesides which can be engaged or hooked by the preferably flexible and/orarm-like holding elements 41. Thus, it is possible to hold or fix thereceptacles 37 at its outer periphery and/or such that any tilting canbe avoided, even when the piercing element 17 is retracted.

It is noted that the carrier 5 preferably comprises a “dummy” receptacle43 without any insert 6 for receiving the piercing element 17 in theinitial transportation state (delivery state) of the dispensing device1, i.e., before first use of the dispensing device 1, wherein theassembly is in the position shown in FIG. 10, but the piercing element17 extends into the dummy receptacle 43.

FIG. 13 shows in a partial, enlarged view of the carrier 5, thepreferably hollow dummy receptacle 43. In particular, the dummyreceptacle 43 is axially open at one side (slit 43 a) and/or is radiallyopen at its inner side so that the piercing element 17 can be axiallyinserted when mounting the dispensing device 1.

Further, FIG. 13 shows that the holding elements 41 are preferablyprovided with undercuts or transversely extending portions at their freeends or other suitable means to surely hold the receptacles 37 betweenthe holding elements 41 by engaging the noses 42.

FIG. 14 shows a partial, enlarged view of the carrier 5 from the otherside.

The dispensing device 1 comprises preferably a lifespan block (LSB).After using or operating the dispensing device 1 for the predeterminednumber of uses (number of doses or inserts 6), in the present embodimente.g., 30 applications, the dispensing device 1 is locked up completelyin order to avoid any further inadvertent applications. Preferably, thedispensing device 1 has multiple independently working LSB locks. Inparticular, the locks are unlockable and/or lock by form-fit.

The first LSB lock may be formed by an abutment, such as a rib 44 asshown in FIG. 14 or the like, on the storage device 4 or its carrier 5.The abutment limits the rotation of the storage device 4/carrier 5 inthat it abuts at a respective stop provided by the housing 26 or anyother suitable, in particular rigid or stationary part of the dispensingdevice 1 when the last insert 6/cavity 7 has been aligned with respectto the air assembly or piercing element 17.

A second LSB lock may be formed by a snap nose 45 formed on the storagedevice 4, in particular, the carrier 5 as shown in FIG. 13, for lockingthe release button 36 in its actuated or depressed position after thelast use of the dispensing device 1. Thus, any further triggering or anyfurther pump operation would be prevented.

A third LSB lock may be formed by a snap hook 46 also provided on thestorage device 4, in particular, the carrier 5, for locking the grip 19in the inner or pushed position (as shown in FIG. 7) when the storagedevice 4/carrier 5 has reached its end position and the storage device4/carrier 5 has reached its last position/receptacle 37. In particular,the grip 19 may hook with one holding arm or two holding arms 57 (shownin FIG. 16) to the snap hook 46 in the locked state.

Preferably, the storage device 4/carrier 5/receptacles 37 interacts withthe air assembly/slider 29 such that a correct alignment of the piercingelement 17 and the respective receptacle 37 or insert 6 is ensuredbefore the piercing element 17 pierces or opens the respectivereceptacle 37, cavity 7 and/or insert 6. For this purpose, the airassembly or slider 29 preferably comprises an engagement portion, inparticular, a fork portion 47 (FIG. 15), which interacts with thestorage device 4, carrier 5 and/or the respective receptacle 37 toachieve the desired (fine) alignment.

In the present embodiment, the engagement portion or fork portion 47protrudes from the air assembly, in particular, from the needle holder30, which is shown in detail in FIG. 15. The engagement portion or forkportion 47 preferably interacts with alignment means or guiding portionsassociated to each insert 6. In the present embodiment, these alignmentmeans or guiding portions are preferably formed by the protrusions 38,which protrude through the recesses 39 and extend outwardly or axiallyfrom the carrier 5. Thus, a direct and optimized (fine) alignment can bepositively achieved between the piercing element 17 and the respectiveinsert 6 with minimal tolerances.

Preferably, the inserts 6 are restricted in their backward movement asalready mentioned so that the piercing element 17 can be retracted anduncoupled from the respective insert in a definitive manner when the airassembly/slider 29 is retracted into the position shown in FIG. 8. Thisrestriction or limitation is preferably achieved by a respective stop orabutment at the storage device 4 or carrier 5. In particular, this stopor abutment is formed by the inner ring wall 40 or any other suitablemeans.

The dispensing device 1 comprises preferably a counter for counting orshowing the used or unused doses or operations. Preferably, the counterdevice is formed by a numbering 48 on the storage device 4, inparticular on the carrier 5 as shown in FIG. 14. The numbering 48 isvisible through a respective window or transparent portion (not shown)of the housing 26.

The dispensing device 1 preferably comprises a means for preventing aback stroke of the air assembly, in particular, of the piercing element17, when discharge of a dose of formulation 2 is triggered (by actuatingrelease button 36) and the spring 28 moves forward and the gas or air isforced through the respective insert 6. Preferably, this means isrealized by respective locking of the grip 19 against pulling. Inparticular, the grip 19 has to be decoupled before it can be pulled. Inthe present embodiment, the decoupling can be achieved by depressing aportion 49 of the grip 19, in particular by pressing opposite portions49 of the grip 19 together so that a respective undercut or snapengagement between the grip 19 and the housing 26 can be unlocked. Inparticular, the grip 19 consists of two grip parts or halves 50 as shownin FIG. 16. Preferably, each half 50 comprises a flexible or depressibleportion 49 with an associated snap portion 51. The snap portion canengage into a recess or undercut 51 a formed in the housing 26 asschematically shown in FIG. 16 to lock the grip 19 in the pushedposition (FIG. 16 shows the grip 19 in the pulled position).

The dispensing device 1 comprises preferably a means for moving orpressing the used inserts 6 back into their respective cavities 7 orreceptacles 37. This means preferably comprises at least one preferablystationary and/or rigid guiding element 52, here, multiple rib-likeguiding elements 52 are arranged inside the housing 26 adjacent to theouter periphery of the storage device 4 and after the mouthpiece 24, inparticular on or in one half 53 of the housing 26 as shown in FIG. 17.Due to the relative movement of the storage device 4 and the housing 26or guiding elements 52, inclined surfaces 52 a of the guiding elements52 press or push the used insert 6 back into the storage device 4 or itsrespective cavity 7 or receptacle 37, preferably in multiple steps.Alternatively or additionally the inclined portions 11 c of the inserts6 may be used to move, press or urge the used inserts 6 back into theircavities 7, in particular, in cooperation with a preferably stationaryguiding element 52 or the like.

In the present embodiment, a locking means is provided for locking thetension element 32 in the retracted position. Here, the locking meanscomprises at least one snap hook or arm 32 a, preferably two or moresnap arms 32 a, that engage into respective undercuts, recesses or snapopenings 32 b that are preferably formed by or in a back shield 32 c ofthe slider 29 or slider frame 31 or vice versa. However, otherconstructional solutions are possible.

The dispensing device 1 is preferably an active powder inhaler, i.e.,the powder is discharged by pressurized gas, in particular air.Nevertheless, the dispensing operation may be triggered by theinhalation or breathing in of a patient. In particular, the dispensingdevice 1 comprises detection means for detecting inhalation or breathingin by the user and/or trigger means for triggering dispensing of therespective dose.

Preferably, the detection means comprises a sensor 55 (FIG. 1) fordetecting at least one of a pressure, a pressure drop, a velocity, anincrease of velocity or any associated value thereof of the air flowingthrough the dispensing device, in particular, through the mouthpiece 24,when a patient breathes in. The respective detection signal indicatingbreathing in by a patient may be used by the trigger means in order totrigger dispensing of the respective dose by means of pressurized gas.In particular, the trigger means comprises a controller 54 and/or avalve 56 associated with the means for pressurizing gas, in particularthe air pump 18, a gas supply line, the piercing element 17 or the likecontrols or triggers the flow of pressurized gas to and through therespective storage chamber 10 or the like for dispensing the respectivedose of formulation 2.

Preferably, the trigger means operates electrically, electronically,pneumatically or mechanically. For example, the detection means andtrigger means may be formed by an appropriate valve 65 that opens thesupply of pressurized gas through the respective receptacle 37, insert 6and/or storage chamber 10 when the pressure in the mouthpiece 24 dropsdue to breathing in of a patient. Then, the valve 56 preferably staysopen until the flow of pressurized gas stops or the gas pressure reachesor drops bellow an appropriate pressure limit. Such a functionality maybe realized without using electric or electronic components.

There are multiple other mechanisms possible. According to anotherembodiment, a sealed outer case can have a flexible diaphragm, e.g.,made of rubber, mounted within its wall with one surface facing theinside and the other exposed to atmosphere. A linkage with mechanicaladvantage (amplification) connects the diaphragm to the tension element32 (FIGS. 8 & 9) or to the valve 56 or any other suitable means tocontrol gas supply. When the user or patient inhales via the mouthpiece24, the sealed case ensures a pressure reduction due to which thediaphragm bends into the case activating or acting on the mechanicallink, and thus, triggers dispensing, in particular, by releasing tensionelement 32, opening valve 56 or the like.

According to another embodiment, a flap can be sealingly positionedwithin the mouthpiece 24 and connected to the tension element 32, thevalve 56 or the like via a linkage with mechanical advantage oramplification. When the user or patient inhales, the air flow/pressuredifference opens or actuates the flap activating or operating the link,and thus, triggers dispensing, in particular, by releasing tensionelement 32, opening valve 56 or the like.

According to another embodiment, an electronic system can be used. Apressure sensitive actuator can be connected to tension element 32 sothat tension element 32 can be released when detecting inhalation orbreathing in of a user or patient.

Preferably, the automatic triggering or dispensing is only possible whenthe dispensing device 1 has been activated and/or dispensing has beenallowed, in particular, by actuating the release button 36 or any otheractuator, before the trigger means may eventually trigger the dispensingwhen breathing in is detected.

Preferably, the grip 19 and the tension element 32 interact directly orindirectly such that the tension element 32 can be moved by pulling thegrip 19 to compress the spring 28, but can move back into the positionwith decompressed spring 28 without movement of grip 19 when triggeringdispensing. For this purpose, the tension element 32 engages preferablyinto a slit portion 58 formed, in particular, by grip 19.

Preferably, the insert 6, the cavities 7 and/or the receptacles 37 areannually arranged. However, any other arrangement, in particular alinear arrangement or the like, is also possible.

In particular, the dispensing device 1 is a preferably oral and/oractive inhaler, a hand-held device and/or preferably only manuallyoperated. Most preferably, the dispensing device 1 is a dry powderinhaler.

Individual features and aspects of the individual embodiments may alsobe combined with one another as desired or used in other constructionsof atomizers, inhalers, dispensers or the like.

Some preferred ingredients and/or compositions of the preferablymedicinal formulation 2 are listed below. As already mentioned, they arein particular powders or liquids in the broadest sense. Particularlypreferably the formulation 2 contains the following:

The compounds listed below may be used in the device according to theinvention on their own or in combination. In the compounds mentionedbelow, W is a pharmacologically active substance and is selected (forexample) from among the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors. Moreover,double or triple combinations of W may be combined and used in thedevice according to the invention. Combinations of W might be, forexample:

W denotes a betamimetic, combined with an anticholinergic,corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist,

W denotes an anticholinergic, combined with a betamimetic,corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist,

W denotes a corticosteroid, combined with a PDE4-inhibitor,EGFR-inhibitor or LTD4-antagonist

W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor orLTD4-antagonist

W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selectedfrom among albuterol, arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,KUL-1248 and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide-   5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol-   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl    4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1    dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric    acid-   8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol-   2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyde-   N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide-   8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one-   8-hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one-   5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea-   4-(2-{6-[2-(2.6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulphonamide-   3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulphonamide-   4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, preferably the bromide salt, oxitropium salts,preferably the bromide salt, flutropium salts, preferably the bromidesalt, ipratropium salts, preferably the bromide salt, glycopyrroniumsalts, preferably the bromide salt, trospium salts, preferably thechloride salt, tolterodine. In the above-mentioned salts the cations arethe pharmacologically active constituents. As anions the above-mentionedsalts may preferably contain the chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts thechlorides, bromides, iodides and methanesulphonates are particularlypreferred.

Other preferred anticholinergics are selected from among the salts offormula AC-1

wherein X⁻ denotes an anion with a single negative charge, preferably ananion selected from among the fluoride, chloride, bromide, iodide,sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,citrate, fumarate, tartrate, oxalate, succinate, benzoate andp-toluenesulphonate, preferably an anion with a single negative charge,particularly preferably an anion selected from among the fluoride,chloride, bromide, methanesulphonate and p-toluenesulphonate,particularly preferably bromide, optionally in the form of theracemates, enantiomers or hydrates thereof. Of particular importance arethose pharmaceutical combinations which contain the enantiomers offormula AC-1-en

wherein X⁻ may have the above-mentioned meanings. Other preferredanticholinergics are selected from the salts of formula AC-2

wherein R denotes either methyl or ethyl and wherein X⁻ may have theabove-mentioned meanings. In an alternativen embodiment the compound offormula AC-2 may also be present in the form of the free base AC-2-base.

Other specified compounds are:

-   tropenol 2,2-diphenylpropionate methobromide,-   scopine 2,2-diphenylpropionate methobromide,-   scopine 2-fluoro-2,2-diphenylacetate methobromide,-   tropenol 2-fluoro-2,2-diphenylacetate methobromide;-   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,-   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,-   tropenol 4,4′-difluorobenzilate methobromide,-   scopine 4,4′-difluorobenzilate methobromide,-   tropenol 3,3′-difluorobenzilate methobromide,-   scopine 3,3′-difluorobenzilate methobromide;-   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;-   tropenol 9-fluoro-fluorene-9-carboxylate methobromide;-   scopine 9-hydroxy-fluorene-9-carboxylate methobromide;-   scopine 9-fluoro-fluorene-9-carboxylate methobromide;-   tropenol 9-methyl-fluorene-9-carboxylate methobromide;-   scopine 9-methyl-fluorene-9-carboxylate methobromide;-   cyclopropyltropine benzilate methobromide;-   cyclopropyltropine 2,2-diphenylpropionate methobromide;-   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;-   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;-   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;-   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;-   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide.-   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxy-xanthene-9-carboxylate methobromide;-   tropenol 9-methyl-xanthene-9-carboxylate-methobromide;-   scopine 9-methyl-xanthene-9-carboxylate-methobromide;-   tropenol 9-ethyl-xanthene-9-carboxylate methobromide;-   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,

The above-mentioned compounds may also be used as salts within the scopeof the present invention, wherein instead of the methobromide the saltsmetho-X are used, wherein X may have the meanings given hereinbefore forX⁻.

As corticosteroids it is preferable to use compounds selected from amongbeclomethasone, betamethasone, budesonide, butixocort, ciclesonide,deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone,loteprednol, mometasone, prednisolone, prednisone, rofleponide,triamcinolone, RPR-106541, NS-126, ST-26 and

-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate-   (S)-(2-oxo-tetrahydro-furan-3    S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,-   cyanomethyl    6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylate    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives thereof, the solvates and/or hydrates thereof. Any    reference to steroids includes a reference to any salts or    derivatives, hydrates or solvates thereof which may exist. Examples    of possible salts and derivatives of the steroids may be: alkali    metal salts, such as, for example, sodium or potassium salts,    sulphobenzoates, phosphates, isonicotinates, acetates,    dichloroacetates, propionates, dihydrogen phosphates, palmitates,    pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418,Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide-   (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone-   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid]-2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one-   cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3.4-c]-1,2,4-triazolo[4.3-a]pyridine-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3.4-c]-1,2,4-triazolo[4.3-a]pyridine    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts thereof, the    solvates and/or hydrates thereof. According to the invention the    acid addition salts of the betamimetics are preferably selected from    among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001,MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic    acid,-   1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic    acid-   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts, solvates and/or    hydrates thereof. According to the invention the acid addition salts    of the betamimetics are preferably selected from among the    hydrochloride, hydrobromide, hydroiodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate. By salts or derivatives which the    LTD4-antagonists may optionally be capable of forming are meant, for    example: alkali metal salts, such as for example sodium or potassium    salts, alkaline earth metal salts, sulphobenzoates, phosphates,    isonicotinates, acetates, propionates, dihydrogen phosphates,    palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-to-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention, the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The dopamine agonists used are preferably compounds selected from amongbromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid andviozan, optionally in the form of the racemates, enantiomers,diastereomers thereof, and optionally, in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention the acid addition salts of thebetamimetics are preferably selected from among the hydrochloride,hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selectedfrom among epinastine, cetirizine, azelastine, fexofenadine,levocabastine, loratadine, mizolastine, ketotifen, emedastine,dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine,doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine,promethazine, ebastine, desloratidine and meclozine, optionally in theform of the racemates, enantiomers, diastereomers thereof, andoptionally, in the form of the pharmacologically acceptable acidaddition salts, solvates or hydrates thereof. According to the inventionthe acid addition salts of the betamimetics are preferably selected fromamong the hydrochloride, hydrobromide, hydriodide, hydrosulphate,hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

It is also possible to use inhalable macromolecules, as disclosed inEuropean Patent Application EP 1 003 478 A1 or Canadian PatentApplication CA 2297174 A1.

In addition, the compounds may come from the groups of ergot alkaloidderivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-Vinhibitors, optionally in the form of the racemates, enantiomers ordiastereomers thereof, optionally in the form of the pharmacologicallyacceptable acid addition salts, the solvates and/or hydrates thereof.

Examples of ergot alkaloid derivatives are dihydroergotamine andergotamine.

1. Dispensing device for dispensing a formulation as a spray,comprising: a mouthpiece through which the formulation is delivered as aspray, a storage device with multiple separate and pre-metered doses ofthe formulation in annularly arranged receptacles, each receptaclecomprising a cavity with a moveable insert containing a respective doseof the formulation, each cavity being sealed at an outlet side by aseal, wherein each insert comprises an opening means for facilitatingopening of the seal by movement of the respective insert through theseal, the opening means being located at an outlet opening of one of thecavity and the receptacle and only at one side of the seal at the outletopening so that the seal is pivoted mainly to an opposite side of theoutlet opening by said movement for minimizing potential interference bythe opened seal with flowing of the formulation from the receptacletoward the mouthpiece, and wherein each insert comprises a storagechamber containing said pre-metered doses of the formulation and a ductextending within each insert from an inlet end fixed at a wall of saidstorage chamber to an outlet end fixed at said opening means, saidoutlet end being positioned for directly discharging the formulation asa spray into said mouthpiece.
 2. Dispensing device according to claim 1,wherein the opening means comprises one of a tip portion, an inclined ortapered portion, or a cutting edge.
 3. Dispensing device according toclaim 1, wherein each insert is moveable partly outwardly of thereceptacles by an actuator.
 4. Dispensing device according to claim 1,wherein each cavity is adapted for receiving and guiding the insert. 5.Dispensing device according to claim 1, further comprising a connectingelement that is moveable relative to the receptacles for moving eachinsert.
 6. Dispensing device according to claim 5, wherein theconnecting element is a piercing element for piercing the respectiveinsert and for supplying pressurized gas to dispense the respective doseof the formulation.
 7. Dispensing device according to claim 1, furthercomprising means for pressurizing gas for dispensing the formulation. 8.Dispensing device according to claim 7, wherein the means forpressurizing gas comprises a manually operated air pump.
 9. Dispensingdevice according to claim 8, further comprising a connecting elementthat is moveable relative to the receptacles for moving each insert, andwherein the means for pressurizing gas is moveable together with theconnecting element.
 10. Dispensing device according to claim 7, whereinthe means for pressurizing gas comprises a spring store for compressingthe gas.
 11. Dispensing device according to claim 1, wherein each insertis moveable outward with an outward stroke sufficient to ensure that therespective seal cannot interfere with an outlet of the respectiveinsert.
 12. Dispensing device according to claim 1, wherein thedispensing device is a dry powder inhaler.
 13. Storage device for adispensing device, comprising: multiple separate and pre-metered dosesof a formulation in annularly arranged receptacles, each receptaclecomprising a sealed cavity with a moveable insert containing therespective dose of formulation, each cavity being sealed at an outletopening by a seal, wherein each insert comprises an opening means forfacilitating opening of the seal by movement of the respective insertthrough the seal, the opening means being located at an outlet openingof one of the cavity and the receptacle and only at one side of the sealat the outlet opening so that the seal is pivoted mainly to an oppositeside of the outlet opening by said movement for minimizing potentialinterference by the opened seal with flowing of the formulation from thereceptacle, and wherein each insert comprises a storage chambercontaining said pre-metered doses of the formulation and a ductextending within each insert from an inlet end fixed at a wall of saidstorage chamber to an outlet end fixed at said opening means, saidoutlet end being positioned for directly discharging the formulation asa spray.
 14. Storage device according to claim 13, wherein the openingmeans comprises one of a tip portion, an inclined or tapered portion,and a cutting edge.
 15. Storage device according to claim 13, whereineach insert is moveable partly outwardly of the receptacles and/orradially.
 16. Storage device according to claim 13, wherein thereceptacles are separate parts mounted on a carrier.
 17. Storage deviceaccording to claim 13, wherein each insert is moveable outward with anoutward stroke sufficient to ensure that the respective seal cannotinterfere with an outlet of the respective insert.
 18. Method foropening a storage device with multiple separate and pre-metered doses ofa formulation from inserts in sealed cavities, each cavity being sealedat an outlet opening thereof by a seal, comprising the steps of: openingthe cavities one after the other for dispensing a respective dose offormulation by moving a respective insert through the seal covering theoutlet opening of the respective cavity, rupturing or cutting the sealadjacent to only one side of the outlet opening by an opening means ofthe insert so that the seal is pivoted or bent to the opposite side ofthe outlet opening by said moving of the insert in order to avoid anyinterference of the seal with an outlet of the insert formed at the endof the insert that has been moved through the opening or seal,connecting a storage chamber containing said pre-metered doses of theformulation with a source of pressurized gas so as to deliver theformulation through a duct extending within each insert from an inletend fixed at a wall of said storage chamber to an outlet end fixed atsaid opening means, and directly discharging the formulation as a sprayfrom the outlet end of said duct.